According to modern radiobiological concepts, irreversible radiation damage to a living cell is the consequence of multiple ionizations occurring within or near the DNA molecule over a distance of a few nanometers. Such clustered ionization events can lead to multiple molecular damages within close proximity, some of them causing strand breakage and others various base alternations or losses, which are difficult to repair. Unrepaired or misrepaired DNA damages typically lead to cell mutations or cell death.
The measurement of the number and spacing of individual ionizations in DNA-size volumes can be assumed to one of the most relevant for the specification of what can be termed “radiation quality.” By radiation quality, we refer to measurable physical parameters of ionizing radiation that best correlate to the severity of biological effects caused in living organisms. There are a variety of practical applications for such measurements in radiation protection and monitoring, as well as in radiotherapy.
The monitoring and measurement of radiation quality and the investigation of how it relates to the biological effects of ionizing radiation is of prime importance in many different fields including medicine, radiation protection, and manned space flight. For example, heavy charged particles, including protons, carbon ions, and neutrons produce more complex radiation fields than established forms of radiation therapy (protons and electrons). These newer forms of radiation therapy, which are increasingly being used for the treatment of cancer, require a careful study of radiation quality changing with penetration depth in order to avoid unwanted side effects.
The definition of the merits and risks of these new forms of radiotherapy requires a better understanding of the basic interactions these radiations have with DNA. National and international radiation and environmental protection agencies, e.g., the Nation Council on Radiation Protection and Measurements (NCRP) and the International Commission on Radiological Protection (ICRP), are interested in establishing new standards of radiation quality measurements, which are based on individual interactions of radiation with important biomolecules, most importantly, the DNA.
Further, radiation quality measurements are also essential to predict the risks of human space travel. Predictions of the quality and magnitude of space radiation exposure are still subject to large uncertainties. Nanodosimetric measurements of space radiations or simulated ground-based radiations may help to decrease these uncertainties.
The measurement of local ionization clusters in DNA-size volumes requires the development of novel nanodosimetric devices, as these would be most relevant to assess DNA damage. The results of experimental nanodosimetric studies combined with those of direct radiobiological investigations could provide a better understanding of the mechanisms of radiation damage to cells and the reason why some DNA damage is more serious than others leading to cancer or cell death. They would also provide valuable input for biophysical models of cellular radiation damage. There are a variety of practical applications for such measurements in radiation protection and monitoring, as well as in radiotherapy.
Existing methodologies of dosimetry on a microscopic tissue-equivalent scale use microdosimetric gas detectors, for example, tissue-equivalent proportional counters (TEPCs), which measure the integral deposition of charges induced in tissue-equivalent spherical gas volumes of 0.2–10 μm in diameter, i.e., at the level of metaphase chromosomes and cell nuclei. They cannot be used to measure ionizations in volumes simulating the DNA helix. Furthermore, they provide no information about the spacing of individual ionizations at the nanometer level.
The cavity walls of these microdosimetric counters distort the measurements, which is particularly problematic for cavity sizes below the track diameter. It has been suggested to use wall-less single-electron counters to overcome some of these limitations. However, this method is limited by the fairly large diffusion of electrons in the working gas and can only achieve sensitive volume sizes down to the order of ten tissue-equivalent nanometers. The DNA double helix, on the other hand, has a diameter of 2.3 nm.
It has been suggested in the literature to overcome the limitations of microdosimetric counters through the construction of a dosimeter which would combine the principle of a wall-less sensitive volume with the advantage of counting positive ionization ions, which undergo considerably less diffusion than electrons. This would extend classical microdosimetry into the nanometer domain.
This method, called nanodosimetry, is useful for radiobiology based on the premise that short segments of DNA (approximately 50 base pairs or 18 run long) and associated water molecules represent the most relevant surrogate radiobiological targets for study. Instead of measuring the deposition of charges directly in biological targets, nanodosimetry uses a millimeter-size volume filled with a low-density gas at approximately 1 Torr pressure, ideally, of the same atomic composition as the biological medium. Ions induced by ionizing radiation in the working gas are extracted by an electric field through a small aperture and then accelerate towards a single-ion counter. The sensitive volume of the detector is defined by the gas region from which positive radiation-induced ions can be collected using electric-field extraction. This new method would be useful for determining the biological effectiveness of different radiation fields in the terrestrial and extraterrestrial environment.
The problem with prior nanodosimeters, therefore, is that they have lacked means for measurement of the energy and multi-axis position-sensitive detection of primary particles passing through the nanodosimeter, hindering the ability to perform systematic measurements of ionization clusters within a cylindrical tissue-equivalent volume as a function of these important parameters. Further, a method for calibration of a nanodosimeter, e.g., correlating radiation quality with biological damage, has been unavailable. Therefore, the goals of nanodosimetery described above have been a long felt, but as yet unmet need.
It would be desirable, therefore, to have a nanodosimeter which includes a particle tracking and energy measuring system that is capable of multi-axis position-sensitive detection of primary particles passing through the detector within the nanodosimeter, thereby providing the ability to perform systematic measurements of ionization clusters within a cylindrical tissue-equivalent volume as a function of the position of the primary particle and its energy. Once configured with such a particle tracking and energy measuring system, it would be desirable to be able to calibrate the nanodosimeter to correlate the radiobiological data of DNA damage to radiation quality, thereby relating the physics of energy deposition to radiobiological effects.